The overall objective of this Program Project is to determine the nature and diversity of mechanisms active in the regulation and dysregulation of the immune system in autoimmunities. Such study presupposes that the tools to identify, characterize and manipulate cells, genes and molecules of this system are available to Program Project. Key tools in this analysis are highly specialized transgenic, mutant, homozygous deficient ('gene knock-out') congenic, recombinant and other mutant mouse strains. These strains provide the key reagents for each of the projects in this Program Project, and the availability of this type of genetically altered animal has in general revolutionized the study of immunobiology. These strains will permit clear study of tolerance in vivo and in vitro. Key strains will include TCR+ and Ig-transgenic mice to permit direct analysis of autoreactive T and B cells, 'antigen' transgenic mice in which the tissue-specific expression of a given peripheral antigen provides the experimental system, and 'gene knock-out' mice to provide genetic backgrounds deficient in specific significant aspects of immunity. These strains are crucial to our studies of autoimmunity. This core mouse breeding facility is thus an essential resource for the research proposed in projects 1 to 4.